Facile Michael-type addition of aromatic alcohols to N-(4-acetylphenyl) maleic imide

Article abstract of DOI:10.1007/s11164-012-0932-z

A one-pot, economical, and efficient synthesis of 1-(4-acetylphenyl)-3- aryloxypyrrolidine-2,5-diones has been accomplished in single steps and in satisfactory yields from 1-(4-acetylphenyl)-pyrrole-2,5-diones and aromatic alcohols. All the compounds were characterized by physical, spectroscopic, and elemental analysis.

Full text of DOI:10.1007/s11164-012-0932-z

Res Chem Intermed
DOI 10.1007/s11164-012-0932-z
Facile Michael-type addition of aromatic alcohols
to N-(4-acetylphenyl)maleic imide
•
J. R. Patel B. Z. Dholakiya
Received: 19 September 2012 / Accepted: 14 November 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract A one-pot, economical, and efficient synthesis of 1-(4-acetylphenyl)-3-
aryloxypyrrolidine-2,5-diones has been accomplished in single steps and in satis-
factory yields from 1-(4-acetylphenyl)-pyrrole-2,5-diones and aromatic alcohols. All
the compounds were characterized by physical, spectroscopic, and elemental analysis.
Keywords Oxa-Michael adduct ꢀ N-(4-acetylphenyl)maleic imide ꢀ Hot water
Introduction
Cyclic imides are an important class of molecule known for their diverse array of
bioactivity [1, 2]. This biological activity and the various pharmacological uses of
cyclic imides have been attributed to their unique structural features, which
encouraged us to look for newer and more advantageous methods for their efficient
synthesis. Reported methods for Michael addition to maleimides use either pyridine
as base in ethanol or triethylamine as base in dichloromethane [3–5]. These methods
suffer from disadvantages such as poor yield, long reaction time, and use of
hazardous chemicals and halogenated solvent. To overcome these disadvantages it
is essential to develop reaction conditions that are ecofriendly, highly efficient, give
better yields, and result in faster reaction.
In recent years, reaction in water has become important because of its advantages
over other solvents. Water is one of the most environmentally benign and
inexpensive liquids used in organic synthesis. Moreover, reaction in water is a
J. R. Patel ꢀ B. Z. Dholakiya (&)
Department of Applied Chemistry, S.V. National Institute of Technology, Ichchanath,
Surat 395007, Gujarat, India
e-mail: bzd.svnit@gmail.com
J. R. Patel
e-mail: pateljigar.svnit@gmail.com
123

J. R. Patel, B. Z. Dholakiya
greener approach to synthesis of molecules of interest. Many organic reactions have
been tried and tested in an aqueous medium with mixed results [6–8]. The
insolubility of most organic reagents in water has created a need to improve their
compatibility with water by use of phase-transfer catalysts, surfactants, or ionic
liquids. Nevertheless, there are inherent difficulties in handling such reactions.
With ever increasing interest in greener solvents and exploration of new reactions
in water, we herein report the use of water for Michael addition of aromatic alcohols
to maleimide to afford products in good yield, within short reaction time, and under
neutral conditions without the use of any kind of catalyst.
Experimental
Materials and instrumentation
All reagents were of analytical reagent grade and were used without further
purification. Solvents used were purified by standard procedures before use. Maleic
anhydride, p-aminoacetophenone, and aromatic alcohols were purchased from
Aldrich. Melting points were determined in open capillaries on a Veego (model
VMP-D) electronic apparatus and are uncorrected. To monitor the reactions and to
establish the identity and purity of reactants and products, thin-layer chromatography
was performed on microscope slides (2 cm 9 7.5 cm) coated with silica gel G.
Toluene–acetone and chloroform–methanol were used as mobile phases and spots
were visualized under UV irradiation. Elemental analysis (C, H, N) were performed
with a Perkin–Elmer, USA 2400-II CHN analyser. FTIR spectra (4,000–400 cm-1
)
were recorded on a Shimadzu 8400-S spectrophotometer using KBr disks. Nuclear
magnetic resonance spectra were recorded on a Varian 400-MHz spectrometer using
DMSO or DMF as a solvent and TMS as internal reference (chemical shifts in d ppm).
Synthesis of 40-amino maleimides 3
A mixture of maleic anhydride (1) and p-aminoacetophenone (2) (1:1.1) in diethyl
ether, catalysed by DABCO (1,4-diazabicyclo [2.2.2] octane) (0.5 mol) gave
40-amino maleimide (3) in short reaction time and high yield [9].
O
O
Ar
Water
650C
O
N
Ar
OH
+
N
O
O
O
O
CH3
3
4a-k
5a-k
Scheme 1 Synthesis of 1-(4-acetylphenyl)-3-aryloxypyrrolidine-2,5-diones 5a–k
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A facile approach for the aromatic alcohols Michael-type addition
Table 1 Isolated yield of 1-(4-acetylphenyl)-3-aryloxypyrrolidine-2,5-diones 5a–k
Entry
Ar
Isolated yield (%)
5a
5b
5c
5d
5e
5f
a-Naphthyl
b-Naphthyl
p-Cl–C6H4
85
84
78
76
75
68
70
72
91
93
92
p-Br–C6H4
p-F-C6H4
o-CH3–C6H4
m-CH3–C6H4
p-CH3–C6H4
p-NO2–C6H4
o-COOH–C6H4
o-CHO–C6H4
5g
5h
5i
5j
5k
General procedure for preparation of 1-(4-acetylphenyl)-3 aryloxypyrrolidine-2,5-
diones 5a–k
In a typical experiment, 1-(4-acetylphenyl)-pyrrole-2,5-dione (3) (210 mg, 1 mmol,
1.00 equiv) in a round-bottomed flask containing a 1:1 mixture of demineralized
water and 4-bromophenol (4d) (150 mg, 1 mmol) was heated for 1 h at 60–65 °C.
The reaction mixture was then washed with saturated sodium bicarbonate solution
and extracted with ethyl acetate. The solvent was evaporated under reduced pressure
to furnish the product 1-(4-acetylphenyl)-3-(4-bromophenoxy)pyrrolidine-2,5-
dione, which was washed with hexane and dried under vacuum.
1-(4-Acetylphenyl)-3-(1-naphthyloxy)pyrrolidine-2,5-dione 5a
Brown solid. Yield 85 %; M.p. 145 °C (hexane–MeOH). FTIR (KBr): 1,724, 1,599,
1,520, 1,344. H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.55 (s, 3H);
1
3.11 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.64–8.17 (m, 7H), 7.32 (dd, J = 15, 1H),
7.34 (dd, J = 15, 2H). 13C NMR (500 MHz, DMSO)) 22, 32, 80.8, 103, 120, 120.1,
121.9, 125, 126, 127, 129, 133, 134, 145, 170.9, 191 d ppm; ESIMS m/z 359 (M?)
Anal. Calc. for C22H17NO4 (359.37): C, 73.53; H, 4.77; N, 3.90 Found: C, 73.51; H,
4.75; N, 3.88.
1-(4-Acetylphenyl)-3-(2-naphthyloxy)pyrrolidine-2,5-dione 5b
Brown solid. Yield 84 %; M.p. 147 °C (hexane–MeOH). FTIR (KBr): 1,724, 1,599,
1,520, 1,344. H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.55 (s, 3H);
1
3.11 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52-8.20 (m, 7H), 7.32 (dd, J = 15, 1H),
7.34 (dd, J = 15, 2H). 13C NMR (500 MHz, DMSO) 22.8, 31.1, 80.8, 103.6, 120,
120.3, 121.9, 125, 126, 127, 128.8, 133, 134, 145, 171, 189 d ppm; ESIMS m/z 360
(M ? H) Anal. Calc. for C22H17NO4 (359.37): C, 73.53; H, 4.77; N, 3.90 Found: C,
73.52; H, 4.78; N, 3.91.
123

J. R. Patel, B. Z. Dholakiya
H
H
H
Ar
O
O
O
H
H
CH
Ar-OH
O
O
N
O
O
O
O
N
N
O
CH3
O
CH3
O
CH3
3'
3
TS-I
Ar
O
Ar
O
O
OH
O
O
N
N
O
CH3
O
CH3
5'
5
Scheme 2 Proposed mechanism for addition of aromatic alcohols to maleimide
1-(4-Acetylphenyl)-3-(4-chlorophenyloxy)pyrrolidine-2,5-dione 5c
Yellow solid. Yield 78 %; M.p. 164 °C (hexane–MeOH). FTIR (KBr): 1,724, 1,599,
1,520, 1,344. 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04 (s, 3H); 2.5
(s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55 (dd, J = 10, 1H),
7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H). 13C NMR (500 MHz, DMSO) 22, 71,
82, 114.8, 118, 120, 128, 132.4, 133, 144, 160, 161, 189 d ppm; ESIMS m/z 300
M – 1; 221, M – 2; 144 M – 3; 128 M – 4; Anal. Calc. for C18H14ClNO4 (343.76):
C, 62.89; H, 4.10; N, 4.07 Found: C, 62.86; H, 4.1; N, 4.01.
1-(4-Acetylphenyl)-3-(4-bromophenyloxy)pyrrolidine-2,5-dione 5d
Brown solid. Yield 76 %; M.p. 166 °C (hexane–MeOH). FTIR (KBr): 1,724, 1,599,
1,520, 1,344. 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04 (s, 3H); 2.5
(s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55 (dd, J = 10, 1H),
7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H).13C NMR (500 MHz, DMSO) 22.8,
72.2, 83.2, 115.4, 116.3, 120.3, 128, 132.4, 133, 145, 159, 161, 195 d ppm; ESIMS
123

A facile approach for the aromatic alcohols Michael-type addition
m/z 348 M – 1; 270, M – 2;187 M – 3; 172(M)-4) Anal. Calc. for C18H14BrNO4
(388.21): C, 55.69; H, 3.63; N, 3.61 Found: C, 55.63; H, 3.62; N, 3.63.
1-(4-Acetylphenyl)-3-(4-fluorophenyloxy)pyrrolidine-2,5-dione 5e
Yellow solid. Yield 75 %; M.p. 168 °C (hexane–MeOH). FTIR (KBr): 1,724, 1,599,
1,520, 1,344. 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04 (s, 3H); 2.5
(s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55 (dd, J = 10, 1H),
7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H). 13C NMR (500 MHz, DMSO) 23, 74,
83, 114, 119, 120, 128, 131.8, 133, 147, 161, 164, 193 d; ESIMS m/z 284 M – 1;
265, M – 2; 188 M – 3; 172, M – 4) Anal. Calc. for C18H14FNO4 (327.30):
C, 66.05; H, 4.31; N, 4.28 Found: C, 66.07; H, 4.30; N, 4.29.
1-(4-Acetylphenyl)-3-(2-methylphenyloxy)pyrrolidine-2,5-dione 5f
Brown solid. Yield 68 %; M.p. 105 °C (hexane–MeOH). FTIR (KBr): 1,724, 1,599,
1,520, 1,344. 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04 (s, 3H); 2.5
(s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55 (dd, J = 10, 1H),
7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H). 13C NMR (500 MHz, DMSO) 11,
22.3, 31, 80.7,114, 120 126.9, 127.85, 128, 129, 130.22, 133, 135.9, 137, 138, 163,
167.78, 171 d ppm; ESIMS m/z 324 (M ? H) Anal. Calc. for C19H17NO4 (323.34):
C, 70.58; H, 5.38; N, 4.33 Found: C, 70.56; H, 5. 34; N, 4.31.
1-(4-Acetylphenyl)-3-(3-methylphenyloxy)pyrrolidine-2,5-dione 5g
Brown solid. Yield 70 %; M.p. 149 °C (hexane–MeOH). FTIR (KBr): 1,724, 1,599,
1,520, 1,344. 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04 (s, 3H); 2.5
(s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55 (dd, J = 10, 1H),
7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H). 13C NMR (500 MHz, DMSO) 11, 22,
31, 80,114, 120,126.9, 127.85, 128, 129, 130.22, 133, 135.9, 137, 138, 163, 167.78,
171 d ppm; ESIMS m/z 324 (M ? H) Anal. Calc. for C19H17NO4 (323.34):
C, 70.58; H, 5.38; N, 4.33 Found: C, 70.58; H, 5. 36; N, 4.32.
1-(4-Acetylphenyl)-3-(4-methylphenyloxy)pyrrolidine-2,5-dione 5h
Orange brown solid. Yield 72 %; M.p. 152 °C (hexane–MeOH). FTIR (KBr):
1,724, 1,599, 1,520, 1,344. H NMR (500 MHz, DMSO), 3.45 (DMSO solvent);
1
2.04 (s, 3H); 2.5 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55
(dd, J = 10, 1H), 7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H). 13C NMR
(500 MHz, DMSO) 11.2, 23, 31, 83,114, 120, 126.9, 127.85, 128, 129, 130.22, 133,
135.9, 137, 138, 163, 167.78, 171 d ppm; ESIMS m/z 324 (M ? H) Anal. Calc. for
C19H17NO4 (323.34): C, 70.58; H, 5.38; N, 4.33 Found: C, 70.58; H, 5. 33; N, 4.33.
123

J. R. Patel, B. Z. Dholakiya
1-(4-Acetylphenyl)-3-(4-nitrophenyloxy)pyrrolidine-2,5-dione 5i
Brownish black solid. Yield 91 %; M.p. 98 °C (hexane–MeOH). FTIR (KBr):
1,724, 1,599, 1,520, 1,344. H NMR (500 MHz, DMSO), 3.45 (DMSO solvent);
1
2.04 (s, 3H); 2.5 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55
(dd, J = 10, 1H), 8.32 (dd, J = 15, 1H), 8.34 (dd, J = 15, 2H). 13C NMR
(500 MHz, DMSO) 22.8, 31, 81.7, 114, 120, 126.9, 127.85, 128, 129, 130.22, 133,
135.9, 137, 138, 163, 167.78, 171 d ppm; ESIMS m/z 354 (M ? H) Anal. Calc. for
C18H14N2O6 (354.31): C, 61.02; H, 3.98; N, 7.91 Found: C, 59.99; H, 4.01; N, 7.89.
1-(4-Acetylphenyl)-3-(salicylicacidyloxy)pyrrolidine-2,5-dione 5j
Light brown solid. Yield 93 %; M.p. 115 °C (hexane–MeOH). FTIR (KBr): 1,724,
1,599, 1,520, 1,344. H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04
1
(s, 3H); 2.5 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55
(dd, J = 10, 1H), 7.34 (m, 4H), 10.2 (s, 1H). 13C NMR (500 MHz, DMSO) 22.8,
31, 80.7, 114, 120, 126.9, 127.85, 128, 129, 130.22, 133, 135.9, 137, 138, 163,
167.78, 171, 189 d ppm; ESIMS m/z 355 (M ? 2H) Anal. Calc. for C19H15NO6
(353.32): C, 64.59; H, 4. 28; N, 3.96 Found: C, 64.57; H, 4.29; N, 4.0.
1-(4-Acetylphenyl)-3-(salicyldehydoxy)pyrrolidine-2,5-dione 5k
Light orange solid. Yield 92 %; M.p. 128 °C (hexane–MeOH). FTIR (KBr): 1,724,
1,599, 1,520, 1,344. H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04
1
(s, 3H); 2.5 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55
(dd, J = 10, 1H), 7.32 (m, 4H), 7.34 (dd, J = 10, 2H), 8.7 (s, 1H). 13C NMR
(500 MHz, DMSO), 22.8, 31, 80.7, 114, 120, 121, 126.9, 127.85, 128, 129, 130.22,
133, 135.9, 137, 138, 163, 168, 174 d ppm; ESIMS m/z 337 (M?) Anal. Calc. for
C19H15NO5 (337.32): C, 67.65; H, 4. 48; N, 4.15 Found: C, 67.63; H, 4.46; N, 4.11.
Result and discussion
Maleimides were prepared by condensation of maleic anhydride with different
p-amino acetophenones, using DABCO as catalyst, to give corresponding malei-
mide in excellent yield [9].
As model reaction, 1-(4-acetylphenyl)pyrrole-2,5-dione (3; 200 mg, 1 mmol,
1.00 equiv) and p-bromophenol (150 mg, 1 mmol, 1.00 equiv) were added to a
250-ml, three-necked flask equipped with a Teflon-coated 3.2-cm egg-shaped
magnetic stir bar, internal temperature probe, and reflux condenser and containing
distilled water. The mixture was stirred for 30 min then heated at 60–65 °C internal
temperature for 1 h. After 1 h, TLC analysis revealed the reaction was complete.
The reaction flask was cooled to ambient temperature and the reaction mixture was
transferred to a separating funnel, washed with saturated sodium bicarbonate
solution, and extracted with ethyl acetate. The combined organic layer was dried
over MgSO4 (6,000 mg). The drying agent was removed by filtration and the
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A facile approach for the aromatic alcohols Michael-type addition
organic layer was then concentrated by rotary evaporation (the bath temperature was
increased from 30 to 45 °C at 30–60 mmHg) to yield the crude product as a brown
solid. To generalize the reaction, conjugate addition with different aromatic phenols
was also tried (Scheme 1). The reaction proceeded well in all cases, and the
products were obtained within 1 h and 30 min in 70–93 % yield, as shown in
Table 1.
Hydrogen-bond formation between water and the carbonyl oxygen of maleimide
causes electrophilic activation, making the b position more susceptible to
nucleophilic attack. The oxygen atom of water in turn forms a hydrogen bond
with the phenol hydrogen and increases the electron density at the oxygen, resulting
in activation of nucleophile, which attacks the b position of maleimide. This
mechanism illustrated in Scheme 2 can be assumed to occur via the proposed
transition state TS-I. Thus, hydrogen bonding between the carbonyl oxygen and
water results in an increase in the electrophilicity at the b carbon, and, similarly,
hydrogen bonding between the nucleophile and the water leads to nucleophilic
activation. Thus the dual activation role of water is evident [10].
Conclusion
We have demonstrated that reaction of 1-(4-acetylphenyl)-pyrrole-2,5-diones with
aromatic alcohols via Michael addition, resulting in 1-(4-acetylphenyl)-3-aryloxy-
pyrrolidine-2,5-diones, enables efficient synthesis of the Michael adduct in a single
step with satisfactory overall yield. The products of this reaction are of potential
medicinal interest. This approach has substantial advantages over previously
described methods because of the ready availability of the starting materials and
simple operations.
Acknowledgments The authors thank the S.V. National Institute of Technology, Surat, for the financial
support, and the members of the analytical group of the Central Salt and Marine Chemicals Research
Institute, Bhavnagar, and Oxygen Healthcare Private Ltd, Ahmedabad, Gujarat, India, for spectral
measurements.
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